Transplantation of human islets has great potential as an effective means of treating insulin dependent diabetes mellitus. Primary non-function is the main cause of islet graft failure and it results in the need for multi-donor transplants. We will test the hypothesis that islet engraftment can he enhanced simultaneously by expressing growth factor gene like human Vascular Endothelial Growth Factor (hVEGF) that promotes islet revascularization, and antiapoptotic gene like human interleukin-1 receptor antagonist (hIL-IRa) to prevent apoptosis of transplanted islets in the host. In preliminary studies, higher levels of hVEGF were secreted from human islets transfected with bicistronic adenoviral vector encoding hVEGF and Green Fluorescent Protein (Acv-GFP-hVEGF), while hVEGF secretion from Adv-GFP transfected and mock-transfected islets was very low. Insulin release from transfected islets was comparable to mock-transfected islets. Proapoptotic cytokines IFN-gamma and TNF-alpha did not induce apoptosis when islets were transfected with Adv-GFP-hVEGF. Our specific aims are to determine whether i) adenoviral vectors encoding hVEGF and hIL-IRa (AdvhVEGF- hlL-lRa) will efficiently transfect islets and improve their function; and ii) ex vivo transfection with Adv-hVEGF-hlL-IRa will prevent primary islet nonfunction and reduce the islet mass needed for restoring normoglycemia. The significance of this research is that the proposed ex vivo gene therapy will promote islet revascularization, prevent apoptosis and decrease the number of islets required for achieving normoglycemia. The data will be beneficial to successful human islet transplantation.